rs113042313

Positions:

chr17-37710601-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000458.4(HNF1B):c.1108G>A(p.Gly370Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000142 in 1,614,076 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00045 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 2 hom. )

Consequence

HNF1B
NM_000458.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:2

Conservation

PhyloP100: 4.53

Variant links:

Genes affected

HNF1B (HGNC:11630): (HNF1 homeobox B) This gene encodes a member of the homeodomain-containing superfamily of transcription factors. The protein binds to DNA as either a homodimer, or a heterodimer with the related protein hepatocyte nuclear factor 1-alpha. The gene has been shown to function in nephron development, and regulates development of the embryonic pancreas. Mutations in this gene result in renal cysts and diabetes syndrome and noninsulin-dependent diabetes mellitus, and expression of this gene is altered in some types of cancer. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Sep 2009]

HNF1B links:

LOC124903989 (HGNC:):

LOC124903989 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06089571).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000447 (68/152270) while in subpopulation AFR AF= 0.00159 (66/41554). AF 95% confidence interval is 0.00128. There are 1 homozygotes in gnomad4. There are 34 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 68 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1B	NM_000458.4 linkuse as main transcript	c.1108G>A	p.Gly370Ser	missense_variant	5/9	ENST00000617811.5
LOC124903989	XR_007065732.1 linkuse as main transcript	n.5934C>T		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1B	ENST00000617811.5 linkuse as main transcript	c.1108G>A	p.Gly370Ser	missense_variant	5/9	1	NM_000458.4		P35680-1
HNF1B	ENST00000621123.4 linkuse as main transcript	c.1030G>A	p.Gly344Ser	missense_variant	5/9	1		P1	P35680-2
HNF1B	ENST00000613727.4 linkuse as main transcript	c.1030G>A	p.Gly344Ser	missense_variant	5/7	1
HNF1B	ENST00000614313.4 linkuse as main transcript	c.1108G>A	p.Gly370Ser	missense_variant	5/8	5

Frequencies

GnomAD3 genomes

AF:

0.000427

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00152

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000135

AC:

AN:

251104

Hom.:

AF XY:

0.0000958

AC XY:

AN XY:

135712

show subpopulations

Gnomad AFR exome

AF:

0.00172

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000111

AC:

162

AN:

1461806

Hom.:

Cov.:

AF XY:

0.0000880

AC XY:

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.00299

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000894

GnomAD4 genome

AF:

0.000447

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.000457

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.00159

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000919

Hom.:

Bravo

AF:

0.000563

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000132

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 05, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2021	Observed in patients with MODY or renal cysts and diabetes syndrome; however, additional information is not available (Bellanne-Chantelot et al., 2005; Poitou et al., 2012); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22432796, 28453780, 21163139, 25700310, 27535533, 16249435, 24097065, 32041611) -

HNF1B-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 10, 2024

The HNF1B c.1108G>A variant is predicted to result in the amino acid substitution p.Gly370Ser. This variant has been reported in individuals with maturity-onset diabetes of the young type 5, also referred to as renal cysts and diabetes syndrome (Bellanne-Chantelot et al. 2005. PubMed ID: 16249435; referred to as rs113042313, Elashi et al. 2022. PubMed ID: 36613572). It has also been reported an individual without diabetes (Supplementary Tables 2 and 3, Flannick et al. 2013. PubMed ID: 24097065). No family or functional studies were performed to help assess its pathogenicity. This variant is reported in 0.18% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Renal cysts and diabetes syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

literature only

Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg

Jul 06, 2019

- -

Type 2 diabetes mellitus;C0431693:Renal cysts and diabetes syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Nov 30, 2020

The heterozygous c.1108G>A (p.Gly370Ser) missense variant identified in HNF1B has been previously reported in association with maturity-onset diabetes of the young type 5/ renal cysts and diabetes syndrome [PMID: 16249435;PMID: 2243279;PMID: 24097065]. Functional studies to evaluate the potential pathogenicity of this variant were not performed. This variant has been reported as a variant of uncertain in the ClinVar database [Variation ID:379811]. The variant has 0.001521 allele frequency in the African/African-American subpopulation of the gnomAD(v3) database (63 out of 41,432 heterozygous alleles, 1 homozygous allele). The affected Gly370 residue is not highly conserved and in silico tools provide conflicting interpretations about potential pathogenicity of this variant. Based on the available evidence, the c.1108G>A (p.Gly370Ser) missense variant in the HNF1B gene is reported as a variant of uncertain significance. -

Maturity onset diabetes mellitus in young

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 30, 2017

The p.G370S variant (also known as c.1108G>A), located in coding exon 5 of the HNF1B gene, results from a G to A substitution at nucleotide position 1108. The glycine at codon 370 is replaced by serine, an amino acid with similar properties. This variant was detected in a cohort of individuals with maturity-onset diabetes of young(MODY)/renal cysts and diabetes (RCAD) (Bellanné-Chantelot C et al. Diabetes, 2005 Nov;54:3126-32; Poitou C et al. Transpl. Int., 2012 May;25:564-72). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 17, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Uncertain

0.50

D;.;T;T;.

Eigen

Benign

-0.089

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.86

M_CAP

Pathogenic

0.75

MetaRNN

Benign

0.061

T;T;T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.7

L;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.49

Sift4G

Benign

1.0

T;T;T;T;T

Polyphen

0.23

B;.;.;.;.

Vest4

0.50

MVP

0.76

ClinPred

0.029

GERP RS

5.7

Varity_R

0.54

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over